Human African Trypanosomiasis (HAT) represents a significant public health problem in sub-Saharan Africa affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and high cost. From a collaborative effort between SCYNEXIS, Anacor Pharmaceuticals, Pace University, and DNDi, we report ongoing lead optimization efforts on a novel class of small molecule boron-containing compounds, exemplified by SCYX-6759. These compounds inhibit in vitro growth of T. brucei with IC<sub>50</sub>s ~100 nM, are not cytotoxic to mammalian cells, and exhibit good physiochemical and pharmacokinetic properties. In a murine model of central nervous system (CNS) stage disease utilizing the TREU667 strain of T. b. brucei, treatment with 50 mg/kg of SCYX-6759 BID for 14 days demonstrated 100% efficacy, resulting in absence of blood parasites for >180 days. Development of a structure-activity relationship (SAR) profile for this chemical series and efforts to improve biological and pharmacokinetic profiles in the CNS-disease model through chemical modifications are reported herein.
Jacobs, R.; Ding, C.; Freund, Y.; Jamagin, K.; Plattner, J.; Bacchi, C.; Yarlett, N.; Orr, M.; Nare, B.; Rewerts, C.; Chen, D.; Noe, A.; Sligar, J.; Jenks, M.; Wring, S.; Don, R. Lead Optimization of Novel Boron-Containing Drug Candidates for the Treatment of Human African Trypanosomiasis. Presented at The American Society of Tropical Medicine and Hygiene 58th Annual Meeting, Washington, DC, USA, 18-22 November 2009. (2009)